Selection of different factors for the Calculation of Similarity factor (f2) and Dissimilarity factor (f1) as per different countries' regulatory recommendations for the biowaiver Study: A Systematic Review

 

Sunil Kumar, Dilip Maheshwari

Department of Pharmaceutical Sciences, Lok Jagruti Kendra University, Ahmedabad, Gujarat, India.

*Corresponding Author E-mail: pharmacistsk@rediffmail.com

 

ABSTRACT:

Biowaiver refers to the waiving of bioequivalence studies or in vivo bioavailability. The model-independent similarity factor approach for the dissolution profiling test is considered in the comparison shown in this article survey. Rather than conducting costly and tedious bioequivalence (in vivo) examinations, a dissolution test can be used as an alternative for comparing whether two drug products are identical or not. The purpose of this review is to feature the expectations of various regulatory bodies for biowaiver studies. Initially, no regulatory agency defined the early time point; however, the FDA recently defined the early time point as up to 10 minutes for products with a fast or immediate release rate. The biowaiver approach based on the BCS (Biopharmaceutical Classification System) is intended to reduce the requirement for studies of bioequivalence, so it can provide an alternative to bioequivalence studies. Bioequivalence studies might be waived if in vivo execution can be legitimated by satisfactory dissolution profiling information. The Biopharmaceutical Classification System approach is logical in view of the gastrointestinal permeability, aqueous solubility, and characteristics of the drug molecules. The model-independent similarity factor (f2) method is suggested by numerous regulatory bodies to show dissolution closeness or similarity worldwide. This f2 method is leaned toward on the grounds that it is generally simple to utilize, the similarity factor (f2) value is not difficult to calculate, and a well-known acceptance criteria for profile closeness or f2 (similarity) (i.e., f2≥50) has been set. As per comparison with different regulatory guidelines for dissolution profiling, it was found that there were many divergences in the criteria for exemption from the F2 criteria, the selection of the minimum number of dissolution profile time points, the selection of end time points, and the coefficient of variation. So it is needed to harmonies a guideline on biowaiver studies that can be applicable to all countries for ANDA (Abbreviated New Drug Application) filing purposes.

 

KEYWORDS: Biowaiver, In vitro, Similarity factor, Dissolution, Biopharmaceutical Classification System (BCS), Bioequivalence.

 

 


INTRODUCTION: 

A dissolution test assesses the rate and extent to which a drug substance forms a solution in controlled conditions. Oral Solid dosage forms are commonly prescribed to patients because they are stable, usually safe, and economical. The bioavailability issues are connected with the absorption process of drug products.

 

The absorption of drug substances after taking oral solid dosage form is determined by their solubility, physiological conditions, and permeability across the GIT (gastrointestinal tract). As a result, the significance of the dissolution profile for the establishment of equivalence for medicinal products should be highlighted.1 For developing nations, WHO has also promoted the use of generic products to make them less expensive. A generic replacement could be considered when a generic version of an innovator drug contains the same strength of the same drug molecule in a similar dosage category and same administration route and also meets quality, identity, purity, and strength standards. The similarity factor (f2) method is a moderately straight-forward and widely acknowledged method used to calculate and compare dissolution profiling. As a matter of fact, regulatory bodies required the utilization of the similarity factor method for this purpose. Be that as it may, the guidelines and rules related to the utilization of the similarity factor test are not harmonized globally.2 Biowaiver intends that in vivo studies might be waived. Rather than leading costly and tedious bioequivalence (in vivo) examinations, an in vitro (dissolution) test could be an alternative reason for choice with respect to whether two drug products are the same. Dissolution profile comparison could be done in different test conditions by using the similarity factor calculation method.3

 

METHODS:

A well-validated method should be used for the dissolution profiling study of the innovator product as well as the test product with three different dissolution media, including one release media.

0.1 N HCl or SGF without enzyme

pH 4.5 Acetate Buffer

pH 6.8 phosphate Buffer or SIF without enzyme.

 

The reason behind performing this test is to evaluate the drug product's performance in three media to evaluate the release pattern of drug products in the gastro-intestinal tract, which should be physiologically relevant. In situations where numerous time points and different media tests are required, media selection requires some special consideration. So whenever water is used as the dissolution medium for the test, a proper justification might be required for consideration.3-5

 

For comparison of two drug profiles, Moore and Flanner have given two formulas. These formulas, which are model independent, are called the dissimilarity (f1) and the similarity (f2) factors.2 To get a precise result, it is necessary to collect adequate sampling time points for comparison of both the reference drug and the test. Since the mean value of dissolution tests or profiles is analyzed utilizing these calculation methods, the fluctuation related to the dissolution at each time point should meet the criteria established by different regulatory authorities. The dissimilarity factor evaluates the difference in percent between the two dissolution data sets of profiles at each time point.2,6-8

 

Figure 1: Formula for dissimilarity factor calculation

Where

n = Number of time points

Rt = Mean dissolution value of the References product at time t, and

Tt = Mean dissolution value of the test product at that same time point

 

When the test product and Reference product profiles are identical the f1 value is equal to zero, it’s increases as the two profiles dissimilar

 

“The f2 factor is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent dissolution between the two profiles”:

 

 

Figure 2: Formula for Similarity factor calculation

 

Where,

n = Number of time points

Rt = Mean dissolution value of the Reference product at time t, and

Tt = Mean dissolution value of the test product at that same time point.

 

When the dissolution profiles of two products (reference and test) are identical, the f2 value approaches 100 and decreases as the degree of similarity between the two products decreases. As per many regulatory guidelines, the two product profiles are considered the same or equivalent when the f1 value is less than 15 (0 to 15) and the f2 value is more than 50 (50 to 100).2,6-8

 

For all markets, the condition in the selection of dosage units (12 units) and time points (at least 3 time points that do not include zero time) for reference and test products should be the same.2,3-7,9-14

 

Regulatory Consideration for dissolution profiling as per different countries tabulated below:

 

Table 1: Regulatory consideration for United States15-19

US

Sr. No.

Parameters

Criteria

1

No. of Time points

At least three time points.

2

End or Last time Point Selection

Not more than one mean value >85%, for both test and reference drug products.

3

Coefficient of variation

20% at first (Early) time point and 10% for afterward time points

4

f2 Value

50 to100

5

f2 Exemptions

If more than 85% of drug released in 15 minutes for products reference and test, then it consider as same without any further calculation and evaluation.

 

 

Table 2: Regulatory consideration for Europe2,20-25

Europe

Sr. No.

Parameters

Criteria

1

Minimum No. of Time points

At least three time points (zero excluded).

2

End or Last time Point Selection

Any of the test product or reference product has arrived at 85% dissolution (or asymptote is reached).

3

Coefficient of variation

20% at first (Early) time point and 10% for afterward time points

4

f2 Value

50 to 100

5

f2 Exemptions

If more than 85% of drug released in 15 minutes for products reference and test, then it consider as same without any further calculation and evaluation.

 

Table 3: Regulatory consideration for Japan26-27

Japan

Sr. No.

Parameters

Criteria

1

Minimum No. of Time points

Three time points selection when % drug release is equal or more than 85% in 15 to 30 minutes.

Four time points selection when % drug release is equal or more than 85% in pH 1.2 and 360 minutes in other media.

Eight time points selection when % drug release is 50 to 85% between 30 and 120 minutes in pH 1.2 and 30 to 360 minutes in other media.

Eight time points selection when % drug release is less than 50 between 30 and 120 minutes in pH 1.2 and 30 to 360 minutes in other media.

2

Last time Point Selection

The reference drug has released 85%. Drug substance: percent
released at end time point (or first point of plateau is acceptable)

3

Coefficient of variation

Detail  on absolute difference given in Japanese guidelines

4

f2 Value

50 to 100

5

f2 Exemptions

Japanese guidelines on bioequivalence studies given details idea on f2 exemption.

 

Table 4: Regulatory consideration for Canada28-31

Canada

Sr. No.

Parameters

Criteria

1

Minimum No. of Time points

Sufficient time points selection till 90% of drug release from drug products.

2

Last time Point Selection

Mean value >85%, for both test and reference drug products

3

Coefficient of variation

20% at first (Early) time point and 10% for afterward time points

4

f2 Value

50 to 100

5

f2 Exemptions

If more than 85% of drug released in 15 minutes for products reference and test, then it consider as same without any further calculation and evaluation.

 

 

 

Table 5: Regulatory consideration for Australia2,13,19

Australia

Sr. No.

Parameters

Criteria

1

Minimum No. of Time points

At least three time points (zero not considered).

2

End or Last time Point Selection

Any of the reference or test drug product has reached at 85% dissolution (or on the other hand asymptote is reached).

3

Coefficient of variation

20% at first (Early) time point and 10% for afterward time points

4

f2 Value

50–100

5

f2 Exemptions

If more than 85% of drug released in 15 minutes for products reference and test, then it consider as same without any further calculation and evaluation.

 

Table 6: Regulatory consideration for Brazil32,33

Brazil

Sr. No.

Parameters

Criteria

1

Minimum No. of Time points

At least five time points (zero not considered).

2

End or Last time Point Selection

Not more than one mean value >85%, for both test and reference drug products

3

Coefficient of variation

20% at first (Early) time point and 10% for afterward time points

4

f2 Value

50 to100

 

Table 7: Regulatory consideration for India2,34

India

Sr. No.

Parameters

Criteria

1

Minimum No. of Time points

Sufficient time points to be collected for each product profile to achieve a complete dissolution virtually.

2

End or Last time Point Selection

Achieve virtually complete dissolution

3

f2 Exemptions

Not provided in the guidance.

 

CONCLUSION:

As per comparison with different regulatory guidelines for dissolution profiling, it was found that there were many divergences in the criteria for exemption from the F2 criteria, the selection of the minimum number of dissolution profile time points, the selection of end time points, and the coefficient of variation. In current guidelines, FDA recommends an early time point of less than 10 minutes for immediate release products, which may not be defined by any other regulatory agencies. So it is urgently needed to harmonies a guideline on biowaiver studies that can be applicable to all countries for filing purposes, which helps the formulation developer file in different countries by generating one data set. For ANDA filing, the biowaiver approach is a well-accepted method due to being less time-consuming and cost-saving.

 

ABBREVIATIONS:

BCS: Biopharmaceutical Classification system, FDA: Food and drug administration, HCl: Hydrochloric acid, SGF: Simulated gastric fluid, SIF: Simulated intestinal fluid, ANDA: Abbreviated new drug application

 

ACKNOWLEDGEMENT:

Authors would like to thanks LJ Institute of Pharmacy for helping in preparation of this manuscript.

 

CONFLICT OF INTEREST:

The authors declare that they have no conflict of interest.

 

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Received on 07.12.2022            Modified on 13.03.2023

Accepted on 01.05.2023           © RJPT All right reserved

Research J. Pharm. and Tech 2024; 17(3):1414-1417.

DOI: 10.52711/0974-360X.2024.00224